All posts tagged Davis

There’s been a great deal of controversy and confusion surrounding ME/CFS — even whether it is an actual disease. Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.” Mark Davis

There’s nothing like a high-profile study from a major university. For one thing it can get you publication in one of the most prestigious journals around. The journal the Montoya/Mark Davis study was published in, The Proceedings of the National Academy of the Sciences, is the official publication of the National Academy of Sciences. Its website gets about 21 million hits a month; this study is going to get around.

The study examined the levels of a very large number of cytokines (n=51) in the blood of a very large number of patients and healthy controls (ME/CFS=186; healthy controls= 388). Age, sex, race and something called “nonspecific binding” were accounted for.

This was one study we really didn’t want to fail

One of the biggest ME/CFS immune studies ever undertaken, done at a top University, this was a study that we dearly didn’t want to fail. This is the kind of study likely to be labeled “definitive”. It was on scale with the Columbia cytokine study, where co-authors Ian Lipkin and Mady Hornig analyzed 51 cytokines in 298 patients and 348 healthy controls. If the results of these two hallmark studies were discordant, it would have had negative consequences to any immune interpretation of this disease.

Smaller cytokine studies in ME/CFS have a history of inconsistency, making the similarities in these two studies important.

Results

The first news was not good. The levels of only two cytokines, TGF-Î (elevated) and resistin (lowered) were different in the patients compared with controls. Displaying an unusual level of consistency for ME/CFS, TGF-B has now been found elevated in about six out of the ten studies it’s been tested in.

TGF-B has not received a lot of attention possibly because researchers are not sure what it means. An anti-inflammatory cytokine that can have pro-inflammatory properties, the authors noted that TGF-B is elevated in a number of dissimilar conditions (cancer, liver disease, inflammatory bowel diseases among others). The authors suggested TGF-B may have pro-inflammatory properties in ME/CFS; instead of tamping down inflammation, they proposed it may be “may be a major factor in promoting relentless inflammation.”

Big Finding

“Remarkably, 17 cytokines were associated with severity in ME/CFS patients.” The study authors

Dr. Montoya got the money for the study and conceived it, and Mark Davis advised him on it, was the senior author of the paper, and tested the samples in his lab.

Davis has won a slew of prizes (The Paul Ehrlich Prize, The Gairdner Foundation Prize, The King Faisal Prize, the General Motors Alfred P. Sloan Prize) and is on the Open Medicine Foundation’s Scientific Board. He’s a big deal in the immune world.

Montoya and Davis hit the bulls-eye when they threw severity into the mix

I talked to Davis a couple of days after the study’s publication. I asked him about the main results; those 17 cytokines that predicted severity – was that a lot? It’s an important question. A couple of cytokines popping out might mean that the immune system is involved but is not a major player – time to look someplace else. A lot of cytokines showing up, on the other hand, suggests the immune system may very well be it in ME/CFS – time to dig deeper.

Was 17 cytokines a lot? Even in the staid language of scientific journals the surprise at the size of the effect came through: “Remarkably”, the paper said, “17 cytokines were associated with severity in ME/CFS patients.”

When I asked Davis if it was really a lot, I heard him take a deep breath: “it’s a lot – really a lot” – he said. Getting a third of the immune factors to show up suggests massive immune involvement. Davis – who is involved in constructing immune signatures for different diseases and health – said everything he’s seen about this disease suggests autoimmunity. That’s a particularly meaningful statement from such a well-known immunologist. He’s getting to know ME/CFS pretty well: Montoya’s study is the biggest study his public lab has run.

(Mark Davis has two labs – his private research lab and a larger, more public lab he set up to run many more samples at a time. That lab, which got a big federal grant, was designed to bring the same kind of rigor he uses in his private lab to bigger studies. Researchers like Dr. Montoya can bring their samples to the lab and have the lab test them. That’s what happened in this study)

A Different Kind of Disease?

Mark Davis thinks ME/CFS is probably an autoimmune disease. You don’t see the kind of overt cytokine increases in ME/CFS that are seen in autoimmune diseases like rheumatoid arthritis and lupus. This study, in fact, suggested that cytokines were not increased in the patient group as a whole relative to healthy controls.

Adding severity to the mix, however, suggested that cytokines were heavily involved in this disease. Mark Davis said he’d never seen a disease with mostly normal cytokine levels but which presented such clear indications that cytokines affected symptoms. He suggested that other diseases like Alzheimer’s might display similar patterns if researchers started looking for them.

In an interview with Miriam Tucker, Dr. Montoya echoed the unusual nature of the disease: he simply called the immune activation in ME/CFS – as he has for some time now – a different kind of inflammation.

“Inflammation is much more complicated than two imperfect old measures [sed rate and C-reactive protein]. We’re showing an inflammation that has not been seen before.” Jose Montoya

Three Options?

But what could be causing this bizarre pattern? Higher cytokine levels could certainly explain the more severe fatigue in some ME/CFS patients, but how do the low or normal cytokine levels explain the fatigue in the more moderately fatigued patients? They do have ME/CFS after all; even if they are less ill than the severely ill, they are still enormously fatigued but their cytokine levels aren’t elevated at all. In fact the cytokine levels are lower than normal in some of them. Three options have been suggested.

(1) Loss of Immune Control In the Severely Ill

One possibility the paper presented is that the healthier patients with lower levels of pro-inflammatory cytokines are able to control them to some extent. Their immune systems are grinding away but they’re keeping – probably at some cost – the pro-inflammatory elements under control. The control mechanisms of the sicker patients, though, have collapsed – they’re bearing the burden of unremitting cytokine activity.

(2) A Localized Infection

In conversation Mark Davis suggested that a localized infection could also be causing the immune system to react – not with the huge increases in cytokines seen in systemic inflammatory or autoimmune diseases but with small, harder to detect ones. He’s not the first to suggest that. A couple of years ago Michael Van Elzakker proposed exactly that scenario for ME/CFS.

ME/CFS may be a different kind of inflammatory disorder

Van Elzakker proposed that localized infections – probably involving the vagus nerve – were causing small, hard to detect elevations of cytokines. Meanwhile the infections were playing havoc with the vagus nerve’s ability to communicate sensory and immune information to the brain.

I asked Van Elzakker about the study. He believes the cytokines this study picked up in ME/CFS are probably spillovers from an infection or injury. He cited Robert Dantzer, an important figure in sickness behavior research and pyschoneuroimmunology, who in a (2014) Trends in Neurosciences review, The Neuroimmune Basis of Fatigue agreed that with regard to fatigue:

“The measurement of circulating concentrations of cytokines represents the main limitation of the present studies on fatigue and inflammation. Given that cytokines are autocrine and paracrine communication factors, their circulating levels have little functional value and represent mostly spillover from the site of cytokine production and action.“

Given how profoundly limited many people with ME/CFS are – Van Elzakker believes these localized infections probably exist in the neuroimmune nerves such as the vagus or trigeminal nerves.

There’s another possibility. Gordon Broderick’s modeling work in chronic fatigue syndrome (ME/CFS) suggests that context may be king in the immune system. During a recent phone call Broderick described the co-expression study he did that found a changed immune landscape in ME/CFS. Cytokines such as IL-1b, 2, 4, IFN-Î³, TNF-Î± and IL-10 had larger than expected impacts in ME/CFS patients relative to healthy controls while other cytokines had less impact.

If Broderick’s right, none of the cytokines found in Montoya’s study need to be elevated to have a significant effect – they simply have to be embedded in a dysregulated immune network.

Leptin is Back

This is the second time leptin has shown up in a Stanford study, and the researchers suggested that it might be the keeping the chronic inflammatory state in ME/CFS intact. It turns out that adipokines – cytokines secreted by fat cells – like leptin may be able to trigger neuroinflammation. They’re also found in higher levels in women and may be a particularly important trigger in female dominated inflammatory diseases such as multiple sclerosis.

Duration

In contrast to the Lipkin/Hornig and another study, this study found little evidence of increased cytokine levels earlier in the disease or decreased levels later in the disease. The small numbers of short duration patients (n=30) in the study, however, could have prevented any findings from reaching statistical significance. Interestingly, the study did not find that disease duration was correlated with severity; i.e. patients who had been ill longer were not necessarily worse off.

Diagnostic Test?

Mark Davis suggested the findings might prove the basis for a diagnostic test but in conversation indicated we’re far from one right now. Much more study is needed.

The diagnostic test problem is greater in the low to moderately ill patients who have similar cytokine levels to healthy controls. How to devise a test to distinguish them from the healthy controls with similar cytokine levels is the big question.

Montoya reported that his team was working on a five-cytokine panel that would require a doctor first classifying each patient by severity. If Montoya can devise specific cytokine signatures for each level of severity, a test might be feasible, but it’s clearly going to be a complex undertaking.

Big Study (Too Big?)

Montoya rather courageously put a lot money into an area of research – cytokine analyses – that have had their problems in ME/CFS. As the Lipkin/Hornig study and this study showed, when it comes to immune studies size is definitely better.

While it is possible that this study had more controls than needed, at least Montoya didn’t err on the other side – too few patients; that might have been fatal to this study. Mark Davis thought that given all the noise in the data, that a smaller study might not have found much.

Don’t Think Too Much: the Zen of ME/CFS

In a kind of Zen-like statement Mark Davis cautioned about “thinking too much” about this disease at this point. Davis wasn’t suggesting not inquiring about the disease, but not coming to conclusions about it. We’re not there yet. We’re more in a space of creative inquiry than anything else.

Mark Davis warned against coming to conclusions; more views of ME/CFS is what we really need

Things got even more zen-like when Davis referred to a famous series of paintings called Thirty-six views of Mt. Fuji to underscore where we are with ME/CFS right now. The celebrated series by Japanese artist Hokusai shows Mt Fuji from different perspectives including from at dawn, from a window in a house, from behind a huge wave, etc., etc.

To Davis, ME/CFS is like Mt Fuji; we need to look at it from a lot more angles to fully understand it. The most important thing we can do now is to test, test, test and let the data guide us.

This study may demonstrate that more than anything. It, after all, had four highly unusual results – very little evidence of immune dysregulation compared to healthy controls; massive evidence (17 cytokines!) on the other hand, that the immune system is effecting severity, a substantial number (on the other, other hand) of individuals with low or low-normal cytokine levels, and finally two cytokines with abnormal levels which didn’t have anything to do with severity at all.

This study, then, boosted interest in the immune system in ME/CFS, while raising a lot of questions about it at the same time. A lot of work – a lot of exploratory work – remains to be done to figure this puzzle box of a disease out.

In fact, exploration is largely carrying the day in ME/CFS research. Montoya got hundreds of samples, tested them as widely as possible, analyzed them a bit and then stood back. Ditto with the Ian Lipkin/Mady Hornig immune study, the metabolomics studies from Armstrong and Naviaux, (Naviaux, however, has a hypothesis), Ron Davis and the Open Medicine Foundation with their severe ME/CFS Big Data study, and Avindra Nath and his deep Intramural NIH study. They’re all exploring.

Mark Davis’ talk at Open Medicine Symposium on Saturday should be a good one. NINDS Director Dr. Koroshetz talked up Davis’s exciting findings in the recent NIH Telebriefing, and Ron Davis thinks they may be even more significant than this paper. If you’re at the Symposium you can ask him about his work or Mt Fuji or just say hello and thanks.

Treatment

This study is a major legitimizer and a big spur for more immune studies – particularly big immune studies. One thing it doesn’t present are clear treatment options. When I asked Mark Davis about treatment options, he was unwilling to commit to any line of treatment based on the results. He agreed that basing treatment options off of this study would be like shooting fish in a barrel.

That doesn’t mean the study won’t help on the treatment end. The severity results, after all, scream inflammation. That suggests anti-inflammatories might very well help. Ron Davis noted that many immune affecting drugs are under development right now which might be useful for ME/CFS in the future. We simply need more study to assess which targets might be best.

If Gordon Broderick’s right, though, it may take more than knowing a cytokine’s levels to find the right target. Broderick’s working on complicated models that incorporate the effects hormone levels, in particular sex hormone levels, have on immune factors in ME/CFS. Broderick believes he’ll be able to devise a treatment approach that pushes the immune system one way and then another in order to nudge it back to a stable and healthy state.

Fatigue or Functioning?

While the multi-dimensional fatigue index used to assess fatigue has been validated as a good measure of fatigue across many diseases, one wonders if a functionality scale might have worked better. Fatigue is what ME/CFS is known for, but it’s real impact is on functioning. It’s possible to be very fatigued and still work, or to be pacing effectively – and not doing much work – and be less fatigued.

The MFI worked well in this study and past ME/CFS studies have used it, but one wonders if a scale that tracks functionality – how much activity one is actually doing – might have been more effective at tracking severity.

Slow Progress

Montoya has been given much (reportedly $8 million donation in 2008) and promised much, but the ME/CFS work has been slow. He’s a toxoplasmosis expert, possibly the top expert in the country, and he’s been pouring out toxoplasma studies – fourteen since 2015 – but the work in ME/CFS has gone much slower. Since 2009 he’s been the senior or lead author on just four ME/CFS studies – two of which involved the valganciclovir trial and predated the opening of his ME/CFS center.

This latest study was the most important one – it will undoubtedly help the field – but one hopes that with this monster study out of the way Montoya will be able to move faster on his other ones. His current research projects page lists ten studies. Two involve the Zinns who, unable to publish their work at Stanford, exited to work with Lenny Jason. Those studies are surely not extant.

The eight others, though, involve brain imaging, neuroendocrine, gene expression, cardiovascular, immune and pathogen studies. In a telephone conversation Mark Davis referred to some scintillating results he and Montoya are working on using the immune data Montoya gathered. Let’s hope we’ll see those results and more from Montoya’s Chronic Fatigue Initiative in the not too distant future.

Conclusion

This study, as did the Lipkin/Hornig study, suggested you have to approach ME/CFS differently than other diseases to be successful.

One of the things that emerged from this study is that ME/CFS really, really is different and woe to any researcher who assumes that it’s not. The regular rules of the road do not apply – you can’t just measure cytokine levels and expect to get anything. You have to dig deeper, and what this study and the large Lipkin/Hornig study before it demonstrated was that if you do dig deeper, you might stumble on something extraordinary.

The study’s excellent pedigree – it’s size, the lab it took place in and the journal it was published in – guarantees it will get noticed and that’s a good thing. The most important aspect of the study may be the legitimization it confers on the illness. Hopefully the study will introduce new researchers intrigued by what could be a new type of inflammatory disorder to the field. While more work is needed, the study also points to possible future effective treatment options. Lastly, the study indicates, as did the Lipkin/Hornig study, that bigger really is much, much better in ME/CFS research. Hopefully funders will take a cue from these large studies, and support the bigger and more definitive studies this disease needs to move forward.

The article is a far cry from some of sentiments of the “Life After XMRV” piece Nature did in 2011 in which Simon Wessely asserted that the patients’ reactions to that finding would lead another generation of researchers to avoid ME/CFS research. (He rather memorably suggested that researchers would rather “work on images of Mohammed” than study it.) Even advocates for the disease, though, worried that the controversy would turn off researchers. Others, however, felt that the XMRV finding would galvanize researchers to use new technologies to understand ME/CFS.

They were right. Wessely, it appears, was wrong.

World-Class Researchers Beginning to Take ME/CFS On

The Nature article makes it clear that a major cause for the shift occurring is the presence, for the first time ever, of world-class researchers willing to take ME/CFS on.

Dr. Ian Lipkin, an immunologist with an unmatched resume, has not only lent his name and prestige to this disease, but his Columbia team’s published findings – two of which have outlined dramatic changes in immune functioning in ME/CFS – have been at the center of this shift. The Columbia team’s findings have been built on collaborations with expert clinicians, including Dr. Daniel Peterson and the Simmaron Research Foundation he advises. (Check out the slideshow that dominates the website for Lipkin’s Center for Infection and Immunity (CII): one of the slides simply says, “Chronic Fatigue Syndrome is a biological disease”.)

Ron Davis, with his many awards and the stunning story of his son’s illness, is also reaching deep into the scientific world to find answers. The stunning picture of Davis holding the printed circuit he’s using to decipher ME/CFS could be a metaphor for the search for the answer to ME/CFS itself. The answer is there in that maze somewhere, and it’s going to be technology – probably new technology – that uncovers it.

These two men, with their willingness to publicly take bold stands for this disease, have been at the forefront of the “shift” that appears to be occurring. Both men have had the ear of the NIH Director, Francis Collin. Their credibility has gone far in helping the National Institutes of Health, the largest funder of biomedical research in the country, take a reinvigorated approach to ME/CFS.

Dr. Avi Nath, National Clinical Center, NIH

Next, Nature cites the conclusion from the IOM report’s “expert panel” that chronic fatigue syndrome is an under-studied physiological illness. Then comes mention of the intramural study led by Avindra Nath, the widely published and respected clinical director for the National Institute of Neurological Disorders (NINDS). An infectious neurologist, Dr. Nath is conducting the first intramural study in ME/CFS in decades at the National Institutes of Health Clinical Center. Dr. Lipkin and Dr. Peterson are advisers on this intramural study.

Others could have been mentioned: Mark Davis of Stanford, Derya Unutmaz of the Jackson Laboratory, Lasker Award winner Michael Houghton of the University of Alberta, Patrick McGowan of the University of Toronto and others new to the field. As the names line up, you do get the idea that, as Dr. Nath told Nature, “Researchers are thinking deeply about how to build the field.”

Building the field, of course, is what the NIH’s recent decision to fund three ME/CFS research centers is all about. Yes, much more is needed, but this article, showing up in a highly cited journal, suggests that the tide may be slowing turning where it needs to turn the most – in the research community.

Ian Lipkin and the Center for Infection and Immunity Step Forward

Ian Lipkin is featured twice in the article, first stating:

“We now have a great deal of evidence to support that this is not only real, but a complex set of disorders. We are gathering clues that will lead to controlled clinical trials.”

Lipkin has been a vocal advocate for ME/CFS

Three studies from Lipkin and Hornig at Columbia are expected to be published shortly with one to be published next week. Don’t be surprised if, based on Lipkin’s comments, the CII lays the groundwork for something the chronic fatigue syndrome (ME/CFS) community has been waiting for a long time: evidence of biologically determined subsets, or in Lipkin’s words, direct evidence that ME/CFS is made up of a “complex set of disorders”.

The Simmaron Research Institute / Center For Infection and Immunity Collaboration

Simmaron and the Center for Infection and Immunity: working together to understand ME/CFS

In its efforts to scientifically redefine ME/CFS, the Simmaron Research Foundation regularly partners with Dr. Lipkin’s Center for Infection and Immunity. Recent efforts included the spinal fluid study which showed dramatic alterations in immune functioning in the brain, the immune study which differentiated short from long duration ME/CFS patients, and the gut study about to be published. Simmaron is currently collaborating with the CII on additional phases of spinal fluid research and more.

Stay tuned for a Simmaron/CII study that will help to reshape our understanding of what ME/CFS is and how it should be treated.

The Gut and ME/CFS

The gut with its immense effect on the immune system is proving to be a fertile area of research on ME/CFS (see below). Perhaps no other team has pushed the ME/CFS gut connection more effectively recently than Ian Lipkin and Mady Hornig at the CII.

The Nature piece tantalized us a bit with news from Ian Lipkin that one of those studies showing an unusual pattern of gut flora in people with ME/CFS and IBS will be published soon.

A quick look at what studies have told us (see below) about the gut and chronic fatigue syndrome (ME/CFS) suggests that reduced gut floral diversity, possibly characterized by increased numbers of inflammatory bacteria may be common in ME/CFS.

Importantly, every study that has looked for leaky gut – which involves the translocation of gut bacteria into the blood – where it could spark an immune response causing fatigue, pain and other symptoms – has found it. Most intriguingly, the research suggesting that exercise may negatively affect ME/CFS patients’ gut flora and increase their leaky gut issues could help explain post-exertional malaise.

The Gut and ME/CFS – Recent Findings

Exercise in ME/CFS produces changes in gut flora, leaky gut and Inflammation – Shukla’s 2015 study suggests that exercise not only changes the composition of the gut flora in people with ME/CFS but results in increased levels of gut bacteria leaking into the blood (possibly causing inflammation and post-exertional malaise.) The fun didn’t stop there. The ME/CFS patients also had more trouble clearing the gut bacteria from their blood than the healthy controls.

People with ME/CFS have reduced gut flora diversity and leaky gut – Gilotreaux’s 2016 study suggests more pro-inflammatory and fewer anti-inflammatory gut species are present in ME/CFS, and provides more evidence of bacteria sneaking through the gut lining and ending up in the blood.

Gut bacteria/viruses are infectious triggers in ME/CFS – Navaneetharaja’s 2016 review paper suggests that gut bacteria and/or viruses have been overlooked in the search for an infectious trigger in ME/CFS.

Antibiotics can improve gut flora and sleep in some ME/CFS patients – Jackson’s 2015 Australian study suggests that erythromycin improved the gut flora and sleep in about a third of ME/CFS patients but not in the rest.

Altered gut flora diversity – Fremont’s 2013 study shows increased abundance of the same bacterial family (Firmicuties) in ME/CFS as found in Shukla’s 2015 study.

Leaky gut is associated with an autoimmune process – Maes 2013 study suggests that increased bacterial translocation (leaky gut) is associated with high levels of antibodies targeting serotonin. Patients with these antibodies had evidence of increased inflammation.

Leaky gut is associated with inflammation and symptom severity – Maes 2012 study suggests ME/CFS patients are mounting a very strong immune response to intestinal bacteria found in the blood that is leading to increased inflammation.

IBS/leaky gut subset is present in ME/CFS – Maes 2012 study shows one subset of ME/CFS patients (60%) has leaky gut and IBS while another subset does not.